8 things we now know about the toxicity of gadolinium to the brain

When it comes to imaging the nervous system, nothing but an MRI will do for the fastidious neurologist. CT has its uses, such as in detecting acute intracranial bleeding, but it lacks the sophistication to detect or differentiate between less glaring abnormalities. It also comes with a hefty radiation dose. MRI on the other hand, relying on powerful magnetic fields, is a ‘cleaner’ technology.

SLEIC 6. Penn State on Flickr. https://www.flickr.com/photos/pennstatelive/4946556307

MRI scans on their own are however often insufficient to sate the craving of the neurologist for precision. A plain MRI scan, for example, will not tell if a multiple sclerosis lesion is old or new, and it may fail to detect subtle but significant lesions such as low grade brain tumours or lymphoma. Many lesions on routine MRI scan are also ill-defined and non-specific, and could pass for abscesses, vasculitis, inflammation or just small vessel disease (wear and tear) changes.

The Brain. I has it. Deradrian on Flickr. https://www.flickr.com/photos/mgdtgd/3507973704

To silence the niggling doubts, the neurologist often requests an MRI scan with contrast. The idea is to use a dye to separate the wheat from the chaff, the active lesions from the silent ones. This works because sinister lesions have a bad and dangerous habit of disrupting the blood brain barrier. All such insurgencies across the hallowed BBB is sacrilege, a sign that something serious is afoot, (or is it underfoot?). Contrast dyes, on the other hand, are adept at detecting these breaches, traversing them, and staining the sinister lesion in the process. This stain appears on the MRI scan as contrast enhancement. MRI with contrast is therefore invaluable, and a positive study is a call to arms.

By © Nevit Dilmen, CC BY-SA 3.0, Link

Without any doubt, gadolinium is the favoured dye for contrast MRI scans. Gadolinium (Gd) is a lanthanide rare earth metal and it is one of the heavier elements of the periodic table with atomic number 64. It is named after the thrice-knighted Finnish chemist Johan Gadolin, who also discovered the first rare earth metal, yttrium.

Periodic table model. Canada Science and technology Museum on Flickr. https://www.flickr.com/photos/cstmweb/4888243867

We know a lot about some of the risks of injecting gadolinium into the body, such as its tendency to accumulate in people with kidney impairment (who cannot excrete it efficiently). We also know that it may cross the placenta to damage the developing baby. These are however hazards with simple and straight-forward solutions: avoid gadolinium in pregnancy, and don’t use it in people with poor renal function.

By Hi-Res Images ofChemical Elements – http://images-of-elements.com/gadolinium.php, CC BY 3.0, Link

Much more challenging is the problem of gadolinium deposition in the brain of people with normal renal function. This is concerning because it is unpredictable, and because it has the potential to compromise brain structure and function. This blog has previously asked the question, “Is gadolinium toxic?“. The question remains unanswered, and regulatory agencies are still studying the data to provide guidance to doctors. Patient groups on the other hand have been up in arms, as one would expect, impatiently waiting for answers. What then is the state of play with gadolinium? Should neurologists and their patients really be worried? Below are 8 things we now know about gadolinium and its potential brain toxicity.

By Peo at the Danish language Wikipedia, CC BY-SA 3.0, Link

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1. Gadolinium deposition is related to its insolubility at physiological pH

The toxic potential of gadolinium is thought to be the result of its insolubility at physiological pH. Furthermore, gadolinium competes against calcium, an element fundamental to cellular existence. This competition is obviously detrimental to the body.

064 Gadolinium-Periodic Table of Elements. Science Activism on Flickr. https://www.flickr.com/photos/137789813@N06/22951789105

2. The less stable gadolinium agents are the most toxic

There are two forms of gadolinium based contrast agents (GBCAs): the less stable linear GBCAs, and the more stable macrocyclic GBCAs. The linear GBCAs are more toxic, of which Gadodiamide (Omniscan) stands out. Other linear agents are gadobenate dimeglumine (MultiHance), gadopentetate dimeglumine (Magnevist), gadoversetamide (OptiMARK), gadoxetate (Eovist), and gadofosveset (Ablavar). The macrocyclic GBCAs, even though safer, are not entirely blameless. They include gadobuterol (Gadavist), gadoterate meglumine (Dotarem), and gadoteridol (ProHance). Therefore, choose your ‘gad’ wisely.

By زرشکOwn work, CC BY-SA 3.0, Link

 

3. Gadolinium deposits in favoured sites in the brain

It is now established that gadolinium deposits in three main brain areas. The most favoured site is the dentate nucleus of the cerebellum. Other popular regions are the globus pallidus and the pulvinar. This deposition is, paradoxically, visible on plain T1-weighted MRI scans where it shows as high signal intensity.

By Polygon data were generated by Database Center for Life Science(DBCLS)[2]. – Polygon data are from BodyParts3D[1], CC BY-SA 2.1 jp, Link

4. The risk of deposition depends on the number of injections

The risk of gadolinium deposition in the brain is higher with multiple administrations. Stated another way, and to stretch this paragraph out a bit longer, the more frequently contrast injections are given, the higher the chances gadolinium will stick to the brain. The possible risk threshold is 4 injections of gadolinium. The fewer the better…obviously!

Number-04. StefanSzczelkun on Flickr. https://www.flickr.com/photos/stefan-szczelkun/3931901057

5. Gadolinium also deposits outside the brain

The favoured site of gadolinium deposition outside the brain is the kidney, where it causes nephrogenic systemic fibrosis, a scleroderma-like disorder. This however occurs mostly in people with renal impairment. Gadolinium also deposits in other organs outside the brain including bone, skin, and liver. (Strictly speaking, this item has nothing to do with the brain, but it helped to tot up the number to 8 in the title of this blog post, avoiding the use of the more sinister se7en).

By JudgefloroOwn work, CC BY-SA 4.0, Link

 6. Harm from gadolinium brain deposition has not been established

Whilst we know for sure that gadolinium deposits in the nervous system, harm from deposition has not been definitively established. There are, however, reports that gadolinium deposition may produce muscle and eye symptoms, and chronic pain. There are also reports of cognitive impairment manifesting as reduced verbal fluency.

Words words words. Chris Blakeley on Flickr. https://www.flickr.com/photos/csb13/4276731632

7. Precautions may reduce the risk of gadolinium brain deposition

The current recommendation is not to withhold the appropriate use of gadolinium, but to observe simple precautions. Sensibly, use GBCAs only when absolutely necessary. Also consider preferentially using macrocyclic GBCAs and evaluate the necessity for giving repeated GBCA administrations.

 

By IntropinOwn work, CC BY-SA 3.0, Link

 

8. There are emerging ways to avoid gadolinium toxicity

The safest use of gadolinium is not to use it at all. There are some developments in the pipeline to achieve this, although probably not in the very near future. Such developments include manganese based contrast agents such as Mn-PyC3A. A less definitive option is to mitigate the effects of gadolinium by using chelating agents; two such potential agents are nanoparticles and 3,4,3-LI(1,2-HOPO).

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Why not get the snapshot view of gadolinium toxicity in the neurochecklist:

Gadolinium-based contrast agent (GBCA) toxicity

…and leave a comment!

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MRI scan. NIH Image Gallery on Flikr. https://www.flickr.com/photos/nihgov/30805879596

What is the value of temporal artery biopsy in the diagnosis of GCA?

Giant cell arteritis (GCA) is a nasty inflammatory disorder that affects the large arteries. Because it characteristically involves the temporal artery, this form of vasculitis is also referred to as temporal arteritis. It usually affects people over the age of 50 years and manifests with sudden onset headache, scalp pain, and a thick, tender temporal artery. GCA is often accompanied by polymyalgia rheumatica (PMR) , a painful condition of the joints and muscles. The active systemic inflammation in GCA is often detected by the erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) tests. These distinguishing features constitute most of the diagnostic criteria for GCA.

By National Institute of Standards and Technology – https://www.flickr.com/photos/usnistgov/5828207621/, Public Domain, Link

Most people with GCA however do not have all the ‘classical’ features of the disease. A high index of suspicion is therefore required to sniff out the duplicitous miscreant. It is particularly imperative to make the diagnosis as early as possible to prevent the dreaded complications of GCA, sudden blindness and stroke. The treatment of GCA, implemented according to established treatment guidelines, involves several months of oral steroids, drugs which cause immune suppression and a host of other side effects. It is therefore essential that the diagnosis of GCA is made correctly to avoid putting the patient on a long, risky, and unnecessary treatment.

By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 508, Public Domain, Link

The conventional method of establishing the definitive diagnosis of GCA is by performing a temporal artery biopsy. This involves taking a short segment of the temporal artery as it traverses the temple. This procedure however only confirms the diagnosis of GCA in 1335% of people with the condition. One reason the biopsy has such a poor sensitivity is that it is often performed after treatment has already commenced. Another reason the biopsy is often normal is that the inflammation in GCA occurs in patches, sparing large segments of the artery. Don’t even think about it-taking a longer biopsy segment does not increase the yield of temporal artery biopsy. Put another way, “specimen length is not associated with diagnostic yield of temporal artery biopsy.

By NephronOwn work, CC BY-SA 3.0, Link
What then is the value of the temporal artery biopsy in the diagnosis of GCA? This is the question posed by Bowling et al in their incisive paper titled Temporal artery biopsy in the diagnosis of giant cell arteritis: does the end justify the means? They reviewed 129 temporal artery biopsies and found that the clinical diagnosis of GCA was confirmed in only 13% of cases. Furthermore, the outcome of the biopsy rarely ever influenced the treatment; 87% of those with a normal biopsy result still continued their treatment. The miffed authors therefore rhetorically, and indignantly, asked: “can we justify invasive surgery to all patients on histological grounds when the results may not alter management?” 
Ipswich, Waterfront, Ipswich Campus, The Big Question Mark Sculpture. Martin Pettitt on Flikr. https://www.flickr.com/photos/mdpettitt/8671901426

This is an entirely reasonable question especially because there are other more accurate and less invasive ways of establishing the diagnosis of GCA. These include:

But the answer to the authors’ rhetorical question is anyones guess. It is a sad tradition of medicine that studies such as these take ages to change practice. Indeed I predict the the temporal artery biopsy will sidestep this minor hurdle and simply continue its long and agonising reign. Despair!
By No machine-readable author provided. Spekta assumed (based on copyright claims). – No machine-readable source provided. Own work assumed (based on copyright claims)., Public Domain, Link
You can at least read more on GCA in my previous blog post titled Advances in the management of giant cell arteritis. You may also explore these comprehensive neurochecklistsGiant cell arteritis (GCA): clinical featuresand Giant cell arteritis (GCA): diagnosis and management.

 

FDG. TRIUMF Lab on Flikr. https://www.flickr.com/photos/triumflab/8232448893

 

Advances in the management of giant cell arteritis

Giant cell arteritis (GCA), or temporal arteritis, is an affliction of older people. It results in headache and, more worryingly, blindness and stroke.

By Henry Vandyke Carter - Henry Gray (1918) Anatomy of the Human Body (See "Book" section below)Bartleby.com: Gray's Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352
By Henry Vandyke CarterHenry Gray (1918) Anatomy of the Human Body (See “Book” section below)Bartleby.com: Gray’s Anatomy, Plate 508, Public Domain, https://commons.wikimedia.org/w/index.php?curid=541352

 

The diagnosis of GCA is a clinical one. GCA diagnostic criteria stipulate, amongst other things, onset over the age of 50 years, and inflammation in the blood. A temporal artery biopsy may help to firm up the diagnosis. This is however not always readily available, and often falsely negative. Treatment with steroids is imperative to prevent sudden and irreversible visual loss.

By Nephron - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811
By NephronOwn work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=37300811

 

Not much has changed in the world of giant cell arteritis since I was in medical school. Or so I thought. I couldn’t be more wrong. Here are 3 advances challenging the old order in the management of GCA.

 

1. Antiviral treatment

Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360
Varicella zoster virus. NIAID on Flikr. https://www.flickr.com/photos/niaid/5614251360

The cause of GCA is a mystery. One suspect is varicella zoster virus (VZV), of shingles fame. As shingles is also a disease of older people, it is no surprise that some researchers suspected a link between VZV and GCA. Writing in the Journal of Infectious Diseases in a paper titled Varicella Zoster Virus in Temporal Arteries of Patients With Giant Cell Arteritis, the authors detected VZV in the arteries of people with GCA, but did not pick up even a scent of VZV in control subjects who did not have GCA.

Another paper which strengthened the bond between GCA and VZV is in JAMA Neurology titled Analysis of Varicella-Zoster Virus in Temporal Arteries Biopsy Positive and Negative for Giant Cell Arteritis. The authors of this study found VZV in the temporal arteries of 119 subjects with GCA. On the strength of this finding, the authors suggest GCA should be treated with anti-viral drugs. I am picking up the scent of a guideline on the way.

2. Monoclonal antibodies

B0007277 Monoclonal antibodies Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820
B0007277 Monoclonal antibodies
Wellcome Images on Flikr. https://www.flickr.com/photos/wellcomeimages/5814713820

 

Some researchers, obviously uncomfortable with antiviral drugs, have looked elsewhere for ways to improve the treatment of GCA. And they found a champion in the monoclonal antibody Toclizumab. They published their findings in the Lancet under the title Tocilizumab for induction and maintenance of remission in giant cell arteritis: a phase 2, randomised, double-blind, placebo-controlled trial. The authors showed that adding Toclizumab to steroids in people with GCA led to sustained remission in 85% of cases; only 40% of the people on placebo achieved remission. I didn’t smell a rat here; the evidence seems quite convincing.

3. PET scan imaging

By Hg6996 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860
By Hg6996Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=18889860

 

Temporal artery biopsy is hit and miss because GCA is a patchy process. Furthermore, biopsy is invasive and despised by doctor and patient equally. Ever keen to make things painless, doctors have looked at imaging of the artery as a substitute to biopsy. The imaging modalities on the cards include duplex ultrasound and magnetic resonance imaging (MRI). The prize must, however, go to positron emission tomography (PET) which has great potential as indicated in this review of PET scan in GCA. This suggests that PET scan aids the diagnosis, grading, and follow-up of GCA. Additionally, PET scan also identifies inflammation in other blood vessels. I perceive the end of the days of temporal artery biopsy!